This is an R01 application for funding to identify chromosomal markers linked to drug dependence. The use of illicit, highly addictive drugs is a major public health and legal problem in the United States and around the world. There is an urgent need for new pharmacological treatment options. Since a substantial fraction of the vulnerability to abuse drugs has a genetic basis, determining underlying genetic factors will help identify new targets to therapeutic intervention. One approach used to identify genetic factors in complex traits is to use non-parametric linkage analysis, such as the affected sib pair method. However, it is very difficult to ascertain large numbers of sib pairs concordant for drug abuse/dependence, especially in subjects who are actively abusing hard drugs. The investigators will address this problem by ascertaining a relatively stable group of opiate dependent subjects and their affected siblings in a very large population of methadone maintenance clients. Opiate addicts enrolled in methadone programs are perhaps the most stable group of heavily addicted individuals available for clinical study, since they come to clinic almost every day to pick up methadone, and meet with counselors, social workers, psychiatrists and medical doctors frequently. From a pool of 20,000 clients, they will identify 450 sib pairs who are both being treated in a methadone program. These subjects will be assessed by SCID and various psychological measures to identify psychiatric conditions and personality and temperament traits associated with substance dependence. A two stage, genome-wide search for genetic loci linked to opiate dependence will take place; the first at a 10 centimorgan resolution. Positive markers will be followed up in a second stage, 1-3 centimorgan survey. By the end of the project, which will coincide with the completion of the human genome project, they will be able to analyze all of the specific candidate genes that map to linked markers.